mt_monashmedfandomcom-20200213-history
L0301P41 - Introduction to Pharmacokinetics
Pharmacokinetics *what the body does to the drug Pharmacokinetic Phase of Drug Action #absorption #distribution #metabolism #excretion Importance of Pharmacokinetics Planning: *amounts and timing of drug dose *enables decisions regarding: **route of administration **starting dose ***higher than maintenance dose **frequency of drug administration *avoidance of pharmacokinetic drug interactions *prevention of dose-dependent adverse effects of drugs *treatment and management of overdose *enables attainment of a plasma concentration of drug that is in the therapeutic range Administration Routes of Administration of Drugs *injections (parenterally) **rapid onset, especially IV **three types: intravenous, intramuscular and subcutaneous *oral *sublingual (under the tongue) **allows drug to enter vena cava directly **avoids stomach acid and gut enzymes **e.g. nitroglycerin *rectal **can be fairly rapid **e.g. diazepam for emergency treatment of epilepsy in children *intravaginal **e.g. antifungals for thrush *intraurethral **e.g. prostaglandin for treatment of impotence *transdermal (through the skin) **e.g. nitroglycerin, nicotine-replacement *inhalational **e.g. drugs for treatment of athsma *intranasal **e.g. corticosteroids *topical to skin, eye, ear, etc Preferred Route *for patient compliance: **oral ***much more likely to take medication at the right time, dosage Reasons for Use of Other Routes *drug is unstable or rapidly inactivated in GIT **acid and food in stomach may interfere *absorption compromised by vomiting or disease state *patient is unconscious *don’t want systemic effects (adverse effects) *need for immediate effect - speed Absorption Absorption *getting drug from site of administration to site of action, move to “blood stream” Properties Affecting Absorption/Distribution *pharmaceutical form/route of administration **e.g. tablet, capsule, slow release capsule, suspension, ointment *dispersion and dissolution **e.g. from tablet *lipid solubility / ionisation *molecular shape and size Movement of Drug Across Membranes *passive diffusion across lipid membranes *passive diffusion through aqueous channels *carrier-mediated transport **important for a few drugs that are related to endogenous substances e.g. L-dopa Drug Penetration Across Cell Membranes *commonly occurs by simple diffusion across the lipid bilayer *diffusion occurs if the drug is lipid soluble *lipid solubility is low if the drug is ionised *many drugs are weak acids or weak bases **will be both an ionised and un-ionised form in equilibrium in aqueous solution (ratio depends on pH) **the un-ionised form is able to cross cell membranes *depends on pKa value of the drug **pH where 50% ionised/50% unionised *allows easy treatment of many overdoses *e.g. aspirin - weak acid **add sodium bicarbonate to remove H+ **pushes equilibrium to form more of the ionised form = not easily absorbed Molecular Size and Shape *large bulky molecules diffuse slower than small ones, and are less likely to cross biological membranes *in general, lipid solubility will have a more important influence on diffusion across biological membranes than size/shape   Oral “Bioavailability” *measure of how much drug is absorbed into the systemic circulation *after oral administration *compared with intravenous administration *can be affected by: **pharmaceutical formulation **absorption across gut **“first pass” metabolism in liver Speed of Oral Absorption *depends on: **rate of dispersion/dissolution drug properties **gastric emptying time (affected by presence of food, drink etc) **gastric pH (for weak bases or acids) **intestinal surface area and transit time (i.e. motility)   Delaying Absorption *may be desirable to delay absorption to produce a ‘local’ effect or prolong ‘systemic’ action *examples: **administering adrenaline with local anaesthetic **formulation of insulin with protamine or zinc Ion Trapping *molecules are less able to cross biological membranes when they are ionised *often occurs in the urine (for weak acids) *∴ weak electrolytes (ionisable constituents) will tend to accumulate in the compartment in which they are most highly ionised Distribution Distribution *the path by which the drug reaches its target Affected by: *binding to plasma proteins **mainly to plasma albumin **can substantially reduce the amount of “free” drug **drug molecules that are bound to plasma proteins are generally inactive, cannot enter cells or get to the brain, and are not filtered by the kidney glomerulus **different drugs can bind at the same site on plasma albumin, and can therefore displace each other from binding sites **often take more than one drug at the same time results in higher [ ] of free drug *penetration into extracellular and intracellular fluid, tissues, organs, fat, brain, etc *binding to extravascular sites including tissues Therapeutic Index *ratio of dose of drug producing adverse effects to dose producing desired effect *can be high (desirable) **e.g. penicillin, except in allergic individuals *or low (makes dose critical) **e.g. many anti-epileptic drugs Elimination of Drugs from Site of Action *tissue redistribution via circulation **e.g. the effects of an intravenous sedative may diminish as the drug is redistributed from the brain to tissues with lower resting blood flow such as fat and muscle *biotransformation (metabolism) **e.g. in liver, gut, plasma, kidneys *excretion **e.g. via urine, faeces, bile, lungs Metabolism of Drugs *mainly occurs in liver *makes lipid soluble drugs more water soluble so that they can be excreted via the kidneys *after oral absorption, “first pass” through the liver via portal circulation may reduce drug getting into general circulation *most drug biotransformations are catalysed by liver enzymes *as the drug concentration increases enzymes become saturated, kinetics of removal will then change FROM: **first order: rate of reaction proportional to  drug concentration TO **zero order: rate of reaction is constant and independent of drug concentration  Excretion of Drugs *excretion ≠ clearance **excretion = removal from the body **clearance = drug no longer exists in its active form in the body **if drug does not get metabolised and is excreted, then excretion = clearance Sites of Excretion *kidneys: **major site of excretion of water soluble drugs and water soluble metabolites of lipid soluble drugs *lungs: **remove gases and volatile liquids **e.g. many general anaesthetics *gut: **excreted via bile and/or faeces *sweat, saliva, mucous, tears and milk: **can excrete small amounts of drugs (some drugs in milk can be dangerous to infants)